Abstract
OBJECTIVES: Spinal muscular atrophy (SMA) is a devastating motor neuron disorder caused by homozygous loss of the survival motor neuron 1 (SMN1) gene and insufficient functional SMN protein produced by the SMN2 copy gene. Additional genetic protective modifiers such as Plastin 3 (PLS3) can counteract SMA pathology despite insufficient SMN protein. Recently, Spinraza, an SMN antisense oligonucleotide (ASO) that restores full-length SMN2 transcripts, has been FDA- and EMA-approved for SMA therapy. Hence, the availability of biomarkers allowing a reliable monitoring of disease and therapy progression would be of great importance. Our objectives were (i) to analyse the feasibility of SMN and of six SMA biomarkers identified by the BforSMA study in the Taiwanese SMA mouse model, (ii) to analyse the effect of PLS3 overexpression on these biomarkers, and (iii) to assess the impact of low-dose SMN-ASO therapy on the level of SMN and the six biomarkers. METHODS: At P10 and P21, the level of SMN and six putative biomarkers were compared among SMA, heterozygous and wild type mice, with or without PLS3 overexpression, and with or without presymptomatic low-dose SMN-ASO subcutaneous injection. SMN levels were measured in whole blood by ECL immunoassay and of six SMA putative biomarkers, namely Cartilage Oligomeric Matrix Protein (COMP), Dipeptidyl Peptidase 4 (DPP4), Tetranectin (C-type Lectin Family 3 Member B, CLEC3B), Osteopontin (Secreted Phosphoprotein 1, SPP1), Vitronectin (VTN) and Fetuin A (Alpha 2-HS Glycoprotein, AHSG) in plasma. RESULTS: SMN levels were significantly discernible between SMA, heterozygous and wild type mice. However, no significant differences were measured upon low-dose SMN-ASO treatment compared to untreated animals. Of the six biomarkers, only COMP and DPP4 showed high and SPP1 moderate correlation with the SMA phenotype. PLS3 overexpression neither influenced the SMN level nor the six biomarkers, supporting the hypothesis that PLS3 acts as an independent protective modifier.